The ABCs of Lower Genital Tract
Neoplasia and HIV Infection

By Jean R. Anderson, M.D.
The Hopkins HIV Report:
A bimonthly newsletter for healthcare providers
Volume 9, Number 1, January 1997

It has been well established that HIV-infected women are more likely to be co-infected with human papillomavirus (HPV) than HIV-negative women. In a recent report from the HIV Epidemiology Research Study (HERS), 66% of 565 HIV-infected women had HPV by PCR compared to 34% of 300 HIV-negative women. Furthermore, prevalence of HPV increases with progressive clinical disease and immunologic decline.

HPV infection plays a causative role in a wide spectrum of disease, including condylomata acuminata (genital warts) and lower genital tract intraepithelial and invasive neoplasia. In a prospective cohort study, Chirgwin et al [JID 1995;172:235] found an increased incidence of genital warts in HIV-infected women as compared to HIV-negative controls (8.2 vs. 0.8/100 person years of follow-up). Approximately 25 to 40% of Pap smears are abnormal in HIV-infected women, a 10 to 11 fold increase from rates of abnormal cervical cytology in HIV-negative women. Frequency and severity of abnormal Paps increase as CD4 cell count declines.

Two studies reported in Vancouver help explain the association between HIV, HPV, and lower genital tract neoplasia, particularly with progressive immunosuppression. A report from the HERS of over 800 women demonstrated increased persistence by PCR of the same HPV type over time in HIV-infected women as compared to HIV-negative controls; persistence was correlated with CD4 cell count <200/mm3 and increased HPV viral load. A large cohort study from New York found persistent HPV in almost one-third of HIV-infected women without cervical dysplasia, and more than half of these infections were caused by HPV 16 or 18, "high risk" types for neo-plastic transformation.

Controlled studies have not demonstrated a decrease in the sensitivity or specificity of cervical cytology in HIV-infected women and do not support calls for routine colposcopy in all HIV-infected women. Another report from the HERS found no difference in abnormal cervical biopsies overall between infected and uninfected high risk women with normal Pap smears; however, women with CD4 cell counts <200/mm3 and evidence of HPV by PCR were more likely to have abnormal biopsies despite normal Paps. Limitations of this study include small numbers, largely low-grade lesions, and a cohort in which over 80% of the HIV-infected women had CD4 cell counts >200/mm3. Nevertheless, these data suggest a possible role for HPV-DNA testing and/or screening colposcopy in HIV-infected women with advanced immunosuppression.

Cervical cytology is only a screening tool, and abnormal results require confirmation by colposcopic evaluation and biopsy. The terminology relating to preinvasive cervical disease has evolved in recent years from cervical dysplasia to cervical intraepithelial neoplasia (CIN) to squamous intraepithelial lesions (SIL), all more or less synonymous terms. Each of these terms, in turn, is subdivided by degrees of severity (mild, moderate, severe cervical dysplasia, carcinoma-in-situ; CIN I, II, III; low-grade or high-grade SIL); the more severe the lesion, the greater the likelihood of eventual progression to invasive disease if untreated.

When abnormal cervical cytology is confirmed by finding CIN on biopsy, HIV-infected women have higher rates of cervical dysplasia, higher grade lesions, more extensive cervical involvement, and multisite lower genital tract involvement with intraepithelial disease. Both the presence and severity of cervical disease correlate with CD4 count. The prevalence of both anal and vulvar intraepithelial neoplasia is increased with HIV infection and is also correlated with declining CD4 count.

Standard treatment of cervical dysplasia involves excision or ablation using cryotherapy, laser, electrosurgery (LLETZ -large loop excision of the transformation zone), or cervical cold knife conization (CKC). Several studies have now documented an increased rate of recurrence after treatment in HIV-infected women. In a prospective follow-up study of 127 HIV-infected and 193 uninfected women treated for CIN in New York, 62% of the HIV-infected women developed recurrent disease within 36 months after treatment, compared with 18% of HIV-negative patients. Recurrence rates reached 87% in 41 HIV-infected women with CD4 cell counts <200/mm3.

Invasive cervical cancer is the first gender-specific AIDS indicator condition. Although there is no evidence for increased progression from intraepithelial to invasive disease if adequate screening and treatment programs are in place, HIV-infected women who do develop invasive cervical cancer present at more advanced stages, have poorer responses to standard therapy, and higher recurrence and death rates compared to HIV-negative women of similar stage. Invasive anal and vulvar cancers have also been reported in HIV-infected individuals.

The following recommendations for screening and management reflect our current understanding of the interactions of HIV, HPV, and lower genital tract neoplasia:

  1. Repeat Pap smears twice within the first year of HIV care, and then repeat at least annually if these are normal.

  2. Repeat Paps more frequently in the following situations:
    • previous abnormal Pap
    • history of HPV infection after treatment for abnormality
    • symptomatic HIV/low CD4 cell count (probably <200/mm3)

  3. Refer for colposcopy with atypia or SIL on Pap, history of untreated abnormal Pap, or evidence of HPV; consider screening colposcopy and/or HPV-DNA testing with CD4 cell count <200/mm3. Biopsy should be performed for confirmation of diagnosis.

  4. Carefully examine the entire lower genital tract at each gynecologic exam, regardless of symptoms; biopsy abnormal lesions, including atypical-appearing HPV lesions.

  5. When colposcopy is indicated, examine the entire lower genital tract.

  6. Treatment:

    • High grade lesions should be treated with ablation or excision; cryosurgery should be avoided since recurrence rates appear to be higher with this method.

    • Low grade lesions may be followed closely without treatment; it is unclear how likely these are to progress (and how rapidly) to higher grade vulvar or anal lesions should involve gynencology consultation.

    • After treatment, Pap smears should be repeated every 4 months for the first year, then every 6 months. colposcopy should be repeated yearly.

    • Women with either low-grade or high-grade CIN may be eligible for currently enrolling ACTG clinical trials.

    • Genital warts may be treated with topical chemodestructive agents (podophyllin/podofilox, trichloroacetic acid, 5FU), cryotherapy, or excision or ablation for large volume disease. Adjunctive systemic interferon may be considered. Regardless of the method used, recurrence/persistence rates are high and increased with lower CD4 counts.

This article is from The Johns Hopkins University AIDS Service,
The Hopkins HIV Report: A bimonthly newsletter for healthcare providers.